PROCESS FOR THE PREPARATION OF 10-DESACETOXYBACCATIN III

Abstract: A process for abstracting a C10 hydroxy, acyloxy or sulfonyloxy substituent from a taxane in which the C10 hydroxy, acyloxy or sulfonyloxy substituted taxane is reacted with samarium diiodide.

Description: Process for the preparation of 10-desacetoxy baccatin III BACKGROUND OF THE INVENTION The present invention relates to a process for preparing 10-desacetoxytaxol, 10-desacetoxybaccatin III and derivatives of 10-desacetoxytaxol and 10-desacetoxy- baccatin III. Taxol is a natural product extracted from the bark of yew trees. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is currently undergoing clinical trials against ovarian, breast and other types of cancer in the United States and France and preliminary results have confirmed it as a most promising chemo- therapeutic agent. The structure of taxol and the numbering system conventionally used is shown below; this numbering system is also applicable to compounds used in the process of the present invention. In Colin U.S. Patent No. 4,814,470, it was reported that a taxol derivative, commonly referred to as taxotere, has an activity significantly greater than taxol. Taxotere has the following structure: Although taxol and taxotere are promising chemotherapeutic agents, a need remains for additional chemotherapeutic agents. The tetracyclic core of taxol bears a CIO acetoxy substituent and taxotere bears a CIO hydroxy substituent which, if modified, would lead to the preparation of a series of taxol analogs. To date, however, the selective manipulation of the CIO acetoxy and hydroxy groups has presented a formidable problem. SUMMARY OF THE INVENTION Among the objects of the present invention, therefore, is the provision of an improved process for preparing lO-desacetoxytaxol, 10-desoxytaxotere, 10- desacetoxybaccatin III and derivatives of 10-desacetoxy- taxol and 10-desacetoxybaccatin III. Briefly, therefore, the present invention is directed to a process for the preparation of 10- desacetoxy and 10-desoxy taxanes. According to this process, a taxane having a CIO leaving group such as hydroxy, acyloxy or sulfonyloxy is reacted with samarium diiodide. The CIO leaving group is selectively and nearly quantitatively removed from the taxane. Other objects and features of this invention will be in part apparent and in part pointed out hereinafter. DETAILED DESCRIPTION OF THE INVENTION As used herein "Ar" means aryl; "Ph" means phenyl; "Ac" means acetyl; "Et" means ethyl; "R" means alkyl unless otherwise defined; "Bu" means butyl; "Pr" means propyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "TPAP" means tetrapropylammonium perruthenate; "DMAP" means p-dimethylamino pyridine; "DMF" means dimethylformamide; "LDA" means lithium diisopropylamide; "LHMDS" means lithium hexamethyldi- silazide; "L.AH" means lithium aluminum hydride; "Red-Al" means sodium bis (2-methoxyethoxy) aluminum hydride; "AIBN" means azo- (bis) -isobutyronitrile; "10-DAB" means 10-desacetylbaccatin III; FAR means 2-chloro-l,1,2- trifluorotriethylamine; protected hydroxy means -OR wherein R is a hydroxy protecting group; sulfhydryl protecting group" includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; "amine protecting group" includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and "hydroxy protecting group" includes, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxy- benzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2- methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetra- hydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihalo- acetyl such as chloroacetyl, dichloroacetyl, trichloro- acetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C^g alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981. The alkyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like. The alkenyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkenyl containing from two to six carbon atoms in the . principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. The alkynyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The aryl moieties described herein, either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl. The heteroaryl moieties described herein, either alone or with various substituents, contain from 5 to 15 atoms and include, furyl, thienyl, pyridyl and the like. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, and amido. The acyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups. The sulfonyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups. The substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and moieties described herein, may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens and include, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto. Surprisingly, it has been discovered that taxanes possessing CIO hydroxy, acyloxy such as acetoxy or sulfonyloxy substituents may be selectively and nearly quantitatively converted to the corresponding 10- desacetoxy or 10-desoxytaxane. The CIO hydroxy, acyloxy or sulfonyloxy substituted taxane may have a tricyclic or tetracyclic core and corresponds to the formula: wherein Rj is hydrogen, hydroxy, protected hydroxy or together with R 14 forms a carbonate; R 2 is hydrogen, hydroxy, -OCOR 31 , or together with R 2a forms an oxo; R 2a is hydrogen or together with R 2 forms an oxo; R 4 is hydrogen, together with R 4a forms an oxo, oxirane or methylene, or together with R 5a and the carbon atoms to which they are attached form an oxetane ring; R 4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR 30 , or together with R 4 forms an oxo, oxirane or methylene; R 5 is hydrogen or together with R 5a forms an oxo; R 5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R 5 forms an oxo, or together with R 4 and the carbon atoms to which they are attached form an oxetane ring; R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6a forms an oxo; R 6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 5 forms an oxo; R 7 is hydrogen or together with R 7a forms an oxo; R 7a is hydrogen, halogen, protected hydroxy, -OR 28 , or together with R 7 forms an oxo; R 10 is hydroxy, acyloxy or sulfonyloxy; R 13 is hydroxy, protected hydroxy or R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R : forms a carbonate; R 14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 28 is hydrogen, acyl, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative; R 29 , R 30 and R 31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl; Xi is -0X 6 , -SX 7 , or -NX 8 X 9 ; X 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X 3 and X 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X 5 is -COX 10 , -COOX 10 , -COSXjo, -CONX 8 X 10 , or -S0 2 X n ; X 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative; X 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; X 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl; X, is an amino protecting group; X 10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl; X n is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OX 10 , or -NX 8 X 14 ; and X 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl . The reaction is illustrated in Reaction Scheme 1 wherein Rj - R 14a are as previously defined. The reaction between the taxane and samarium diiodide may be carried out at a temperature between about -78 °C and 100 °C, preferably at or below 0°C, in a solvent, for example, an ether such as tetrahydrofuran, a dipolar aprotic such as HMPA (hexamethylphosphoramide) or DMF (dimethylfor amide) , or combinations thereof. Advantageously, the samarium diiodide selectively abstracts the CIO leaving group; C13 side chains and other substituents on the nucleus remain undisturbed. REACTION SCHEME 1 Preferably, the CIO hydroxy, acyloxy or sulfonyloxy substituted taxane is tetracyclic and corresponds to the formula wherein R 7a is hydrogen, hydroxy, protected hydroxy or - OR 28 ; R , is hydroxy or acetoxy; R 13 is hydroxy, protected hydroxy or R 28 is acyl; R 30 is alkyl; R 31 is monocyclic aryl; and X 1 - X 5 are as previously defined. Most preferably, the taxane is baccatin III, 10-desacetyl baccatin III, taxol, taxotere, or other biologically active taxane having a comparable C13 side chain. Baccatin III and 10-desacetyl baccatin III have the following structures. Baccatin III, 10-desacetyl baccatin III and taxol can be separated from mixtures extracted from natural sources such as the needles, stems, bark or heartwood of numerous Taxus species. Taxotere and other biologically active taxanes may be prepared semi- synthetically from baccatin III and 10-desacetyl baccatin III as set forth in U.S. Patent Nos. 4,924,011 and 4,924,012 or by the reaction of a β-lactam and an alkoxide having the taxane tricyclic or tetracyclic nucleus and a C13 metallic or ammonium oxide substituent. The β-lactams have the following structural formula: wherein X l - X 5 are as defined above and the alkoxides have the formula: wherein R α - R 14a are as previously defined and M comprises ammonium or is a metal optionally selected from the group comprising Group IA, Group IIA and transition metals, and preferably, Li, Mg, Na, K or Ti. Taxanes having a CIO sulfonyloxy substitutent may be prepared by reacting 10-desacetyl baccatin III or other CIO hydroxy substituted taxane with a sulfonyl chloride such as methanesulfonylchloride, benzene- sulfonylchloride or toluenesulfonylchloride and a tertiary amine. Taxanes having CIO acyloxy substituents other than acetate can be prepared using 10-DAB as a starting material as illustrated in Reaction Scheme 2. 10-DAB may readily be protected with a variety of protecting groups at C7 with a silylchloricl.. such as triethylsilylchloride or an acylating agent such as acetic anhydride to yield a 7-protected 10-DAB. The CIO hydrcxy substituent of 7- protected 10-DAB 15 may then be readily acylated with any standard acylating agent to yield derivative 16 having a new CIO acyloxy substituent and, if desired, the C7 protecting group can readily be removed. REACTION SCHEME 2 Olll Acy I at I ng agent HOllll HOllll Taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials. The C2 and/or C4 esters of baccatin III and 10-DA.B can be selectively reduced to the corresponding alcohol(s) using reducing agents such as LAH or Red-Al, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine. Alternatively, the C2 and/or C4 alcohols may be converted to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride. Baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can be prepared as set forth in Reaction Schemes 3-7. To simplify the description, 10-DAB is used as the starting material. It should be understood, however, that baccatin III derivatives or analogs may be produced using the same ■ series of reactions (except for the protection of the CIO hydroxy group) by simply replacing 10-DAB with baccatin III as the starting material. Derivatives of the baccatin III and 10-DAB analogs having different substituents at various positions, for instance Cl, C2, C4, C7, and C13, can then be prepared by carrying out any of the other reactions described herein and any others which are within the level of skill in the art. In Reaction Scheme 3, protected 10-DAB 3 is converted to the triol 18 with lithium aluminum hydride. Triol 18 is then converted to the corresponding C4 ester using Cl 2 CO in pyridine followed by a nucleophilic agent (e.g., Grignard reagents or alkyllithium reagents). Scheme 3 T M T M S OI I I 2 0 1 9 Deprotonation of triol 18 with LDA followed by 5 introduction of an acid chloride selectively gives the C4 ester. For example, when acetyl chloride was used, triol 18 was converted to 1,2 diol 4 as set forth in Reaction Scheme 4. Triol 18 can also readily be converted to the 10 1,2 carbonate 19. Acetylation of carbonate 19 under vigorous standard conditions provides carbonate 21 as described in Reaction Scheme 5; addition of alkyllithiums or Grignard reagents to carbonate 19 provides the C2 ester having a free hydroxyl group at C4 as set forth in 15 Reaction Scheme 3. Scheme 4 Scheme 5 AC 2 0 DMAP As set forth in Reaction Scheme 6, other C4 substituents can be provided by reacting carbonate 19 with an acid chloride and a tertiary amine to yield carbonate 22 which is then reacted with alkyllithiums or Grignard reagents to provide 10-DAB derivatives having new substituents at C2. Scheme 6 5 Alternatively, baccatin III may be used as a starting material and reacted as shown in Reaction Scheme 10. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol 24 is converted to carbonate 25 using Cl 2 CO and pyridine, 10 and carbonate 25 is acylated at CIO with an acid chloride and pyridine to produce carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown) . Acetylation of carbonate 26 under vigorous standard conditions provides carbonate 27 which is then reacted with alkyl 15 lithiums to provide the baccatin III derivatives having new substituents at C2 and CIO. The CIO sulfonyloxy analog may be prepared by reacting carbonate 25 with a sulfonylchloride instead of an acylating agent to produce a CIO sulfonyloxy analog of carbonate 26 and then proceeding as otherwise set forth in Reaction Scheme 10. 5 Scheme 7 LAH TMSOIIII ES TMSOIII TMSOl C7 dihydro and other C7 substituted taxanes can be prepared as set forth in Reaction Schemes 8 and 9. As shown in Reaction Scheme 9, Baccatin III may be converted into 7-fluoro baccatin III by treatment with FAR at room temperature in THF solution. Other baccatin derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-chloro baccatin III can be prepared by treatment of baccatin III with methane 10 sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydro- chloride. REACTION SCHEME 8 HOlll SCH. HOl REACTION SCHEME 9 A wide variety of tricyclic taxanes are naturally occurring, and through manipulations analogous to those described herein, an appropriate side chain can be attached to the C13 oxygen of these substances. Alternatively, as shown in Reaction Scheme 10, 7-O-tri- ethylsilyl baccatin III can be converted to a tricyclic taxane through the action of trimethyloxonium tetra- fluoroborate in methylene chloride solution. The product diol then reacts with lead tetraacetate to provide the corresponding C4 ketone. REACTION SCHEME 10 P COA Recently a hydroxylated taxane (14-hydroxy-10- deacetylbaccatin III) has been discovered in an extract of yew needles (C&EN, p 36-37, April 12, 1993). Derivatives of this hydroxylated taxane having the various C2, C4, etc. functional groups described above may also be prepared by using this hydroxylated taxane. In addition, the C14 hydroxy group together with the Cl 10 hydroxy group of 10-DAB can be converted to a 1,2- carbonate as described in C&EN or it may be converted to a variety of esters or other functional groups as otherwise described herein in connection with the C2, C4, C7, C9, CIO and C13 substituents. 15 The following examples are provided to more fully illustrate the invention. EXAMPLE 1 10-Desacetoxybaccatin III; To a solution of baccatin III (20 mg; 0.034 mmol) in THF (0.09 mL) at 0°C under nitrogen was added a solution of Sml 2 (0.1 M; 0.9 mL; 0.09 mmol) in THF. After stirring 45 minutes at 0°C the flask was opened to the air, and the reaction mixture diluted with ethyl acetate (10 mL) . The mixture was poured into aqueous HC1 (0.2N; 25 mL) , extracted with ethyl acetate, and the extract was washed successively with saturated aqueous NaHC0 3 and brine, dried over Na 2 S0 4 and evaporated. The product was isolated by flash chromatography (Si0 2 ; 80% ethyl acetate- hexanes) affording 16.6 mg (92%) of 10-desacetoxybaccatin III which was recrystallized from CHCl 3 -hexanes . mp 230-232 °C. [α] 25 D= -103.6 (c=0.00195, CHC1 3 ) . IR (cm "1 ) : 3100, 2970, 2950, 2900, 1750, 1710, 1460, 1370, 1320, 1270, 1255, 1110, 980, 890, 760, 700. -nmr (500 MHz, CDC1 3 ) δ 8.11 (dd ; 2H; J=8.4, 1.2 Hz; o-Bz) ; 7.61 (dt; 1H; J=7.5,1.2 Hz; p-Bz); 7.48 (br t; 2H; J=7.8 Hz; m-Bz); 5.66 (br d; 1H; J=6.9 Hz; H-2β) ; 4.98 (br dd; 1H; J=9.4,2; H-5α) ; 4.83 (br; 1H; wl/2 19 Hz; H-13β) ; 4.34 (dt; 1H; J=11.2, 7.8Hz; H-7CC) ; 4.31 (br d; 1H;J=8.4 Hz; H-20α) ; 4.17 (br d; 1H; J=6.9 Hz; H-3α) ; 4.15 (dd; 1H; J=8.4, 1Hz; H-20β); 3.84 (d; 1H; J=15.6 Hz; H-lOα) ; 3.46 (ddd; 1H; J=15.6, 3.7,1.6 Hz; H-lOβ) ; 2.64 (ddd; 1H; J=14.4,9.4, 6.9 Hz; H-6α) ; 2.29 (s; 3H; 4-OAc) ; 2.28 (m; 2H; H-14α and H-14β) ; 1.95 (t; 3H; J=1.6 Hz; 18-Me) ; 1.94 (d, 1H; J=6.8 Hz; 13-OH) ; 1.79 (ddd; 1H; J=14.4, 11.2, 2.1 Hz; H-6β) ; 1.64 (s; 3H; 19-Me) ; 1.58 (s; 1H; 1-OH) ; 1.38 (d; 1H; J=7.8 Hz; 7-OH) ; 1.13 (s, 3H; 16-Me) ; 1.06 (s, 3H; 17-Me) . EXAMPLE 2 7-Triethylsilyl-10-desacetoxybaccatin III; To a stirred solution of 10-desacetoxybaccatin III (10.0 mg; 0.019 mmol) in anhydrous pyridine (0.05 mL) at room temperature and under nitrogen, triethylchloro- silane (15 L; 0.09 mmol) was added and the resulting mixture was stirred at room temperature for 48 h. After diluting with ethyl acetate (5 mL) the mixture was poured into saturated aqueous NaHC0 3 (25 mL) and extracted with ethyl acetate. The extract was washed successively with water, 10% aqueous CuS0 4 and brine, dried over Na 2 S0 4 and evaporated. The product was purified by flash chromatography (Si0 2 ; 40% EA-hexanes) affording 11.1 mg (91%) of 7-triethylsilyl-10-desacetoxybaccatin III. EXAMPLE 3 10-Desaσetoxytaxol; To a stirred solution of taxol (35 mg; 0.041 mmol) in THF (0.1 mL) at 0 °C under nitrogen was added a solution of Sml 2 (0.1 M; 1.0 mL; 0.10 mmol) in THF. After stirring 45 minutes at 0 °C the flask was opened to the air and the reaction mixture diluted with ethyl acetate (10 mL) . The mixture was poured into aqueous HC1 (0.2N; 25 mL) , extracted with ethyl acetate, and the extract was washed successively with saturated aqueous NaHC0 3 and brine, dried over Na 2 S0 4 and evaporated. The product was isolated by flash chromatography (Si0 2 ; 80% ethyl acetate- hexanes) affording 29.4 mg (90%) of 10-desacetoxytaxol. EXAMPLE 4 (68-3) Preparation of 3 '-desphenyl-3 '- (2-thienyl) -N-desbenzoyl- N- (t-butoxycarbonyl) -10-desacetoxy taxol. To a solution of 7-O-triethylsilyl-10- desacetoxy baccatin (III) (47.5 mg, 0.073 mmol) in 0.7 mL of THF at -45°C was added dropwise 0.08 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-l-t-butoxycarbonyl-3-triethylsilyloxy- 4- (2-thienyl) -azetidin-2-one (70.0 mg, 0.182 mmol) in 0.7 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC0 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 64.3 mg of a mixture containing (2'R,3'S)-2 ' ,7-(bis) -O-triethylsilyl- 3'-desphenyl-3 '- (2-thienyl) -N-desbenzoyl-N- (t-butoxy¬ carbonyl)-10-desacetoxy taxol and a small amount of the (2'S,3'R) isomer. To a solution of 64.3 mg (0.056 mmol) of the mixture obtained from the previous reaction in 3.2 mL of acetonitrile and 0.15 mL of pyridine at 0 °C was added 0.50 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 46.3 mg of material which was purified by flash chromatography to give 40.1 mg (91%) of 3 '-desphenyl-3 '- (2-thienyl) -N- desbenzoyl-N- (t-butoxycarbonyl) -10-desacetoxy taxol, which was recrystallized from methanol/water. m.p.l58-160°C; [α] » -58, 4° (c 0.0028, CHC1,) . Η NMR (CDC1 3 , 300 MHz) δ 8.11(d, J=6.9 Hz, 2H, benzoate ortho), 7.61(m, IH, benzoate para), 7.50(m, 2H, benzoate meta) , 7.27 (dd, J=5.5, 1.2 Hz, IH, thienyl) , 7.06(d, J=3.3 Hz, IH, thienyl), 7.01 (dd, J=5.7, 3.9 Hz, IH, thienyl) , 6.13(td, J=6.3, 0.9 Hz, IH, H13), 5.70(d, J=6.9 Hz, IH, H2), 5.49(d, J=9.2 Hz, IH, NH) , 5.34(d, J=9.9 Hz, IH, H3 ' ) , 4.62(dd, J=5.4 2.1 Hz, IH, H5), 4.30(d, J=8.1 Hz, IH, H20α) , 4.29(s, IH, H2 ' ) , 4.17(d, J=8.1 Hz, IH, H20β) , 4.06(d, J=6.9 Hz, IH, H7) , 3.81(d, J=15.3 Hz, HlOα), 3.51(d, J=6.6 Hz, IH, H3) , 3.41(m, IH, 2'OH) , 2.61(m, IH, H6α) , 2.36(s, 3H, 4Ac) , 2.30(m, IH, HlOβ), 2.17 (br s, IH, 7 OH), 2.06 (m, IH, H14α), 1.81 ( , IH, H14β) , 1.76(br s, 3H, Mel8), 1.66(s, IH, 1 OH), 1.62(m, IH, H6β) , 1.35(s, 9H, 3Me t-buthoxy), 1.25(s, 3H, Mel7), 1.19(s, 3H, Mel9), 1.17(s, 3H, Mel6) . EXAMPLE 5 (68-4) Preparation of 3 ' -desphenyl-3 '- (isobutenyl) -N-desbenzoyl- N- (t-butoxycarbonyl) -10-desacetoxy taxol. To a solution of 7-O-triethylsilyl-10- desacetoxy baccatin (III) (50.0 mg, 0.077 mmol) in 0.8 mL of THF at -45°C was added dropwise 0.09 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-1-t-butoxycarbonyl-3- (2-methoxyiso- propyloxy) -4- (iso-butenyl)azetidin-2-one (58.0 mg, 0.193 mmol) in 0.7 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC0 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 62.7 mg of a mixture containing (2 'R, 3 'S) -2 ' -O- (2-methoxyiso- propyl) -70-triethylsilyl-3 '-desphenyl-3 ' - (isobutenyl) - N-desbenzoyl-N- (t-butoxycarbonyl) -10-desacetoxy taxol and a small amount of the (2'S,3'R) isomer. To a solution of 62.7 mg (0.059 mmol) of the mixture obtained from the previous reaction in 3.5 mL of acetonitrile and 0.16 mL of pyridine at 0 °C was added 0.55 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 51.5 mg of material which was purified by flash chromatography to give 43.0 mg (95%) of 3 ' -desphenyl-3 '- (isobutenyl) -N- desbenzoyl-N- (t-butoxycarbonyl) -10-desacetoxy taxol, which was recrystallized from methanol/water. m.p.l53-155°C; [α] » Na -56.3° (c 0.003, CHC1 3 ) . Η NMR (CDC1 3 , 300 MHz) δ 8.10 (d, J=7.3 Hz, 2H, benzoate ortho) , 7.60 (m, IH, benzoate para), 7.47 (m, 2H, benzoate meta), 6.15(td, J=8.5, 1.8 Hz, IH, H13) , 5.69(d, J=6.9 Hz, IH, H2) , 5.32(d, J= 9.2 Hz, IH, NH) , 4.93(dd, J=9.6, 1.8 Hz, IH, H5) , 4.82 (d, J=8.7 Hz, IH, Me,C=CH-), 4.76(td, J=8.7, 2.7 Hz, IH, H3 ' ) , 4.37(d, J=8.7 Hz, IH, H20α) , 4.22(d, J=8.7 Hz, IH, H20β) , 4.18(d, J=2.7 Hz, IH, H2 ' ) , 4.03(d, J=7.3 Hz, IH, H7) , 3.82(d, J=15.2 Hz, IH, HlOα) , 3.47(m, IH, 2'OH) , 3.41(d, J=6.6 Hz, IH, H3) , 2.60(m, IH, H6α) , 2.39(m, IH, HlOβ) , 2.37(s, 3H, 4Ac) , 2.18(s, IH, 7 OH), 2.08(m, IH, H14α), 1.78(m, IH, Hl4β), 1.76 (s, 3H, Mel8), 1.74 (s, 6H, 2Me from isobuthenyl) , 1.63 (m, IH, H6β), 1.36 (s, 9H, 3Me t-buthoxy) 1.26 (s, 3H, Mel7), 1.18 (s, 3H, Mel9), 1.15(s, 3H, Mel6) . EXAMPLE 6 ( 69 -1 ) Preparation of N-desbenzoyl-N- (t-butoxycarbonyl) - 10-desacetoxy taxol. To a solution of 7-O-triethylsilyl-10- desacetoxy baccatin (III) (50.0 mg, 0.077 mmol) in 0.8 mL of THF at -45 °C was added dropwise 0.09 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-l-t-butoxycarbonyl-3-triethylsiloxy- 4-phenylazetidin- 2-one (67.5 mg, 0.193 mmol) in 0.8 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC0 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 72.0 mg of a mixture containing (2'R,3 ' S ) -2 ' ,7- (bis) -O-triethylsilyl- N-desbenzoyl-N- (t-butoxycarbonyl) -10-desacetoxy taxol and a small amount of the (2'S,3'R) isomer. To a solution of 72.0 mg (0.071 mmol) of the mixture obtained from the previous reaction in 3.8 mL of acetonitrile and 0.17 mL of pyridine at 0 °C was added 0.60 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25°C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 57.4 mg of material which was purified by flash chromatography to give 39.4 mg (71%) of N-desbenzoyl-N- (t-butoxycarbonyl) - 10-desactoxy taxol, which was recrystallized from methanol/water. m.p.l45-147°C; [α] » Na -54.4° (c 0.0027, CHC1,) . Η NMR (CDCl,, 300 MHz) δ 8.11(d, J=7.1 Hz, 2H, benzoate ortho), 7.61-7.23 (m, 8H, benzoate, phenyl), 6.13 (td, J=6.3, 0.9 Hz, IH, H13), 5.68(d, J=6.9 Hz, IH, H2) , 5.43(d, J=9.2 Hz, IH, NH) , 5.26(d, J=9.9 Hz, IH, H3 ' ) , 4.96(dd, J=5.4 2.1 Hz, IH, H5) , 4.31(d, J=8.1 Hz, IH, H20α) , 4.22(s, IH, H2 ' ) , 4.18(d, J=8.1 Hz, IH, H20β) , 4.03 (d, J=6.9 Hz, IH, H7) , 3.81(d, J=15.1 Hz, HlOα), 3.43 (m, IH, 2 OH), 3.40(d, J=6.6 Hz, IH, H3) , 2.60 ( , IH, H6α) , 2.38 (s, 3H, 4Ac) , 2.32 (m, IH, HlOβ), 2.15(br s, IH, 7 OH), 2.09 {m, IH, Hl4α) , 1.83 (m, IH, H14β) , 1.78 (br s, 3H, Mel8), 1.66(s, IH, 1 OH) , 1.63(m, IH, H6β) , 1.36(s, 9H, 3Me t-butoxy) , 1.25(s, 3H, Mel7), 1.18(s, 3H, Mel9) , 1.16(s, 3H, Mel6) . EXAMPLE 7 (69-2) Preparation of 3 ' -desphenyl-3 '- (2-furyl) -N-desbenzoyl- N- (t-butoxycarbonyl) -10-desacetoxy taxol. To a solution of 7-O-triethylsilyl-10- desacetoxy baccatin (III) (50.0 mg, 0.077 mmol) in 0.8 mL of THF at -45 °C was added dropwise 0.09 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-l-t-butoxycarbonyl-3-triethylsiloxy- 4- (2-furyl) azetidin-2-one (72.8 mg, 0.195 mmol) in 0.8 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC0 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 69.4 mg of a mixture containing (2 'R, 3 'S) -2 ' ,7- (bis) -O-triethylsilyl- 3 ' -desphenyl-3 ' - (2-furyl) -N-desbenzoyl-N- (t-butoxy¬ carbonyl) -10-desacetoxy taxol and a small amount of the . (2'S,3'R) isomer. To a solution of 69.4 mg (0.068 mmol) of the mixture obtained from the previous reaction in 3.8 mL of acetonitrile and 0.17 mL of pyridine at 0 °C was added 0.60 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 59.0 mg of material which was purified by flash chromatography to give 41.0 mg (76%) of 3 '-desphenyl-3'- (2-furyl) -N-desbenzoyl-N- (t-butoxycarbonyl) -10-desacetoxy taxol, which was recrystallized from methanol/water. m.p.l51-153°C; [α] » Na -56.5° (c 0.0025, CHC1,) . Η NMR (CDC1 3 , 300 MHz) δ 8.11 (d, J=7.3 Hz, 2H, benzoate ortho), 7.60(m, IH, benzoate para), 7.49 (m, 2H, benzoate meta) , 7.41 ( , IH, furyl), 6.37 (m, IH, furyl), 6.34(m, IH, furyl), 6.13 (dd, J=6.3, 0.9 Hz, IH, H13) , 5.69(d, J=6.6 Hz, IH, H2), 5.49(d, J=9.2 Hz, IH, NH) , 5.34(d, J=9.9 Hz, IH, H3 ' ) , 4.62(dd, J=5.4, 2.1 Hz, IH, H5), 4.30(d, J=8.1 Hz, IH, H20α) , 4.29(s, IH, H2 ' ) , 4.17(d, J=8.1 Hz, IH, H20β), 4.06(d, J=6.9, IH, H7) , 3.81(d, J=15.3 Hz, IH, HlOα), 3.51(d, J=6.6 Hz, IH, H3) , 3.41(m, IH, 2'OH), 2.61 (m, IH, H6α) , 2.36(s, 3H, 4Ac) , 2.32 (m, 2H, H14α) , 2.28 (m, IH, HlOβ), 2.17 (br s, IH, 70H) , 2.14(m, IH, Hl4α), 1.82 (m, IH, H14β), 1.76 (br s, 3H, Mel8), 1.66 (s, IH, 1 OH), 1.62 (m, IH, H6β) , 1.35(s, 9H, 3Me t-butoxy) , 1.25(s, 3H, Mel7), 1.19(s, 3H, Mel9), 1.16(s, 3H, Mel6) . EXAMPLE 8 (72-1) Preparation of 3'-desphenyl-3'- (isobutenyl) -N-desbenzoyl- N- (t-butoxycarbonyl) -7-deshydroxy-10-desacetoxy taxol. To a solution of 7-deshydroxy-10-desacetoxy baccatin (III) (28.7 mg, 0.051 mmol) in 0.7 mL of THF at -45°C was added dropwise 0.06 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-1-t-butoxycarbonyl-3-(2-methoxyisopropyloxy) -4- (isobutenyl)azetidin-2-one (47.3 mg, 0.15 mmol) in 0.7 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHC0 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 40.3 mg of a mixture containing (2'R,3'S) -2'-O- (2-methoxyisopropyl) - 3'-desphenyl-3'- (isobutenyl)-N-debenzoyl-N- (t-butoxy¬ carbonyl) -7-deshydroxy-10-desacetoxy taxol and a small amount of the (2'S,3'R) isomer. To a solution of 40.3 mg (0.046 mmol) of the mixture obtained from the previous reaction in 3.2 mL of acetonitrile and 0.15 mL of pyridine at 0 °C was added 0.47 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 35.2 mg of material which was purified by flash chromatography to give 24.0 mg (70%) of 3'-desphenyl- 3'- (isobutenyl) -N-debenzoyl-N- (t-butoxycarbonyl) -1 - deshydroxy-10-desacetoxy taxol, which was recrystallized from methanol/water. m.p.l22-125°C; [α]»Na-64.3° (c 0.0025, CHC1,) . Η NMR (CDCl,, 300 MHz) δ 8.12 (d, J=7.1 Hz, 2H, benzoate ortho), 7.60 (m, IH, benzoate para), 7.48 (m, 2H, benzoate meta) , 6.11(td, J=8.1, 1.8 Hz, IH, H13) , 5.68(d, J=6.9 Hz, IH, H2), 5.23(d, J=9.9 Hz, IH, NH) , 5.12(d, J=9.9 Hz, IH, H3 ' ) , 4.96(dd, J=9.1, 2.7 Hz, IH, H5) , 4.80(d, J=8.7 Hz, IH, Me 2 C=CH-), 4.58(dd, J=5.7, 2.1 Hz, IH, H2 ' ) , 4.30(d, J=8.1, IH, H20α) , 4.19(d, J=8.1 Hz, IH, H20β) , 3.97(d, J=6.9 Hz, H3), 3.83(d, J=16.5, IH, HlOα), 3.33 (m, IH, HlOβ) , 3.30 (m, IH, 2'OH), 2.39(m, IH, Hl4α) , 2.35(s, 3H, 4Ac), 2.26(m, IH, H14β), 2.19 (m, IH, H6α) , 2.10 ( , IH, H7α) , 1.95(m, IH, H6β) , 1.73(s, 3H, Mel8), 1.69(s, 6H, 2Me from isobuthenyl) , 1.63 (s, 3H, Mel9), 1.44 ( , IH, H7β) , 1.39 (br. s, IH, 1 OH), 1.35 (s, 9H, 3Me t-buthoxy), 1.25(s, 3H, Mel6), 1.15(s, 3H, Mel7). EXAMPLE 9 ( 72 -2 ) Preparation of 3 '-desphenyl-3 '- (2-thienyl)-N-desbenzoyl- N- (t-butoxycarbonyl) -7-deshydroxy-lO-desacetoxy taxol. To a solution of 7-deshydroxy-10-desacetoxy baccatin (III) (25.0 mg, 0.044 mmol) in 0.7 mL of THF at -45 °C was added dropwise 0.05 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-l-t-butoxycarbonyl-3-triethylsilyloxy-4- (2- thienyl)-azetidin-2-one (50.0 mg, 0.13 mmol) in 0.7 mL of THF was added dropwise to the mixture. The solution was warmed to 0°C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 35.4 mg of a mixture containing (2'R,3'S)-2'-O-triethylsilyl-3'- desphenyl-3'- (2-thienyl) -N-desbenzoyl-N- (t-butoxy¬ carbonyl) -7-deshydroxy-10-desacetoxy taxol and a small amount of the (2'S,3'R) isomer. To a solution of 35.4 mg (0.037 mmol) of the mixture obtained from the previous reaction in 3.2 mL of acetonitrile and 0.15 mL of pyridine at 0 °C was added 0.47 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 32.4 mg of material which was purified by flash chromatography to give 20.5 mg (71%) of 3 ' -desphenyl- 3 ' - (2-thienyl) -N-desbenzoyl-N- (t-butoxycarbonyl) -1 - deshydroxy-10-desacetoxy taxol, which was recrystallized from methanol/water. m.p.l32-134°C; [α] » N_> -61.3° (c 0.0025, CHC1,) . Η NMR (CDCl,, 300 MHz) δ 8.14(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m, IH, benzoate para), 7.51 (m, 2H, benzoate meta) , 7.29(dd, J=5.4, 1.2 Hz, IH, thienyl), 7.09(d, J=3.3 Hz, IH, thienyl) , 7.01(dd, J=5.4, 3.3 Hz, IH, thienyl), 6.14(td, J=8.4, 1.8 Hz, IH, H13) , 5.69(d, J=6.9 Hz, IH, H2), 5.24(d, J=9.9 Hz, IH, NH) , 5.19(d, J=9.9 Hz, IH, H3 ' ) , 4.93(dd, J=9.3, 2.7 Hz, IH, H5), 4.62(dd, J=5.7, 2.1 Hz, IH, H2 ' ) , 4.31(d, J=8.1, IH, H20α) , 4.21(d, J=8.1 Hz, IH, H20β) , 3.98(d, J=6.9 Hz, H3), 3.84(d, J=16.5, IH, HlOα), 3.38(m, IH, HlOβ) , 3.33(m, IH, 2'OH), 2.40(m, IH, Hl4α) , 2.37(s, 3H, 4Ac) , 2.27 (m, IH, H14β), 2.20 (m, IH, H6α) , 2.11 (m, IH, H7α) , 1.95 (m, IH, H6β) , 1.74(s, 3H, Mel8), 1.71(s, 3H, Mel9), 1.46(m, IH, H7β) , 1.40 (br. s, IH, 1 OH), 1.34 (s, 9H, 3Me t-buthoxy) , 1.24(s, 3H, Mel6), 1.13(s, 3H, Mel7) . EXAMPLE 10 ( 72 -3 ) Preparation of 3'-desphenyl-3'- (2-furyl) -N-desbenzoyl- N- (t-butoxycarbonyl) -7-deshydroxy-10-desacetoxy taxol. To a solution of 7-deshydroxy-10-desacetoxy baccatin (III) (35.0 mg, 0.061 mmol) in 0.8 mL of THF at -45°C was added dropwise 0.07 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-l-t-butoxycarbonyl-3-triethylsilyloxy-4-(2-furyl) - azetidin-2-one (68.0 mg, 0.18 mmol) in 0.7 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 56.3 mg of a mixture containing (2'R,3'S) -2'-O-triethylsilyl-3'-desphenyl-3'- (2-furyl) - N-desbenzoyl-N- (t-butoxycarbonyl) -7-deshydroxy-10- desacetoxy taxol and a small amount of the (2'S,3'R) isomer. To a solution of 56.3 mg (0.06 mmol) of the mixture obtained from the previous reaction in 4.6 mL of acetonitrile and 0.22 mL of pyridine at 0 °C was added 0.68 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 48.3 mg of material which was purified by flash chromatography to give 31.7 mg (69%) of 3 ' -desphenyl- 3 ' - (2-furyl) -N-desbenzoyl-N- (t-butoxycarbonyl) -7-des- hydroxy-10-desacetoxy taxol, which was recrystallized from methanol/water. m.p.l28-131°C; [α] » Na -66.9° ( c 0.0028, CHC1,) . l H NMR (CDCl,, 300 MHz) δ 8.13 (d, J=6.9 Hz, 2H, benzoate ortho), 7.60 (m, IH, benzoate para) , 7.48 (m, 2H, benzoate meta) , 7.40(m, IH, furyl), 6.38(m, IH, furyl), 6.32 ( , IH, furyl), 6.12(td, J=8.1, 1.8 Hz, IH, H13) , 5.67(d, J=6.9 Hz, IH, H2), 5.22(d, J=9.9 Hz, IH, NH) , 5.17(d, J=9.9 Hz, IH, H3 ' ) , 4.91(dd, J=9.1, 2.7 Hz, IH, H5), 4.60(dd, J=5.7, 2.1 Hz, IH, H2 ' ) , 4.28(d, J=8.1, IH, H20α) , 4.21(d, J=8.1 Hz, IH, H20β), 3.95(d, J=6.9 Hz, H3), 3.82(d, J=16.5, IH, HlOα), 3.33 ( , IH, HlOβ), 3.31(m, IH, 2'OH), 2.38(m, IH, H14α) , 2.35(s, 3H, 4Ac) , 2.23 (m, IH, H14β), 2.20(m, IH, H6α) , 2.11 ( , IH, H7α) , 1.94 (m, IH, H6β) , 1.73(s, 3H, Mel8), 1.71(s, 3H, Mel9), 1.43 (m, IH, H7β) , 1.38 (br. s, IH, 1 OH) , 1.32 (s, 9H, 3Me t-buthoxy), 1.23(s, 3H, Mel6) , 1.12(s, 3H, Mel7) . EXAMPLE 11 (72-4) Preparation of N-desbenzoyl-N-(t-butoxycarbonyl) -7- deshydroxy-10-desacetoxy taxol. To a solution of 7-deshydroxy-10-desacetoxy baccatin (III) (28.0 mg, 0.049 mmol) in 0.7 mL of THF at -45 °C was added dropwise 0.06 mL of a 0.98 M solution of LiN(SiMe 3 ) 2 in hexane. After 0.5 h at -45 °C, a solution of cis-l-t-butoxycarbonyl-3-triethylsilyloxy-4- (phenyl) - azetidin-2-one (56.0 mg, 0.15 mmol) in 0.7 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 38.4 mg of a mixture containing (2'R,3'S) -2'-O-triethylsilyl-N-desbenzoyl-N-(t-butoxy- carbonyl) -7-deshydroxy-lO-desacetoxy taxol and a small amount of the (2'S,3'R) isomer. To a solution of 38.4 mg (0.041 mmol) of the mixture obtained from the previous reaction in 3.2 mL of acetonitrile and 0.15 mL of pyridine at 0 °C was added 0.46 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at .25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 33.8 mg of material which was purified by flash chromatography to give 27.4 mg (71%) of N-desbenzoyl- N- (t-butoxycarbonyl) -7-deshydroxy-10-desacetoxy taxol, which was recrystallized from methanol/water. m.p.l35-138°C; [α] » Na -65.2° (c 0.0025, CHCl,) . Η NMR (CDCl,, 300 MHz) δ 8.12 (d, J=7.1 Hz, 2H, benzoate ortho), 7.60 (m, IH, benzoate para), 7.51(m, 2H, benzoate meta) , 7.42-7.29(m, 5H, phenyl), 6.12(td, J=8.1, 1.8 Hz, IH, H13), 5.66(d, J=6.9 Hz, IH, H2) , 5.21(d, J=9.9 Hz, IH, NH) , 5.16(d, J=9.9 Hz, IH, H3 ' ) , 4.92(dd, J=9.1, 2.7 Hz, IH, H5), 4.58(dd, 3=5 .1 , 2.1 Hz, IH, H2 ' ) , 4.30(d, J=8.1, IH, H20α) , 4.21(d, J=8.1 Hz, IH, H20β) , 3.97(d, J=6.9 Hz, H3), 3.82 (d, J=16.5, IH, HlOα), 3.41(m, IH, HlOβ), 3.36(m, IH, 2'OH), 2.40(m, IH, Hl4α) , 2.38(s, 3H, 4Ac), 2.26 (m, IH, H14β), 2.20 (m, IH, H6α) , 2.13 (m, IH, H7α) , 1.93 (m, IH, H6β) , 1.73(s, 3H, Mel8), 1.70(s, 3H, Mel9), 1.43 (m, IH, H7β) , 1.38(br. s, IH, 1 OH), 1.32 (s, 9H, 3Me t-buthoxy), 1.25(s, 3H, Mel6), 1.15(s, 3H, Mel7). EXAMPLE 12 Taxanes 68-3, 68-4, 69-1, 69-2, 72-1, 72-2, 72- 3, and 72-4 of Examples 4-11 were evaluated in .in vitro cytotoxicity activity against human colon carcinoma cells HCT-116. Cytotoxicity was assessed in HCT116 cells by XTT (2,3-bis(2-methoxy-4-nitro-5- sulfophenyl) -5- [ (phenylamino)carbonyl] -2H-tetrazolium hydroxide) assay (Scudiero et al, "Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines", Cancer Res. 48:4827-4833, 1988). Cells were plated at 4000 cells/well in 96 well microtiter plates and 24 hours later drugs were added and serial diluted. The cells were incubated at 37°c for 72 hours at which time the tetrazolium dye, XTT, was added. A dehydrogenase enzyme in live cells reduces the XTT to a form that absorbs light at 450 nm which can be quantitated spectrophotometrically. The greater the absorbance the greater the number of live cells. The results are expressed as an IC 50 which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 450 nm) to 50% of that of untreated control cells. All compounds had an IC 50 less than 0.1, indicating that they are cytotoxically active.

Claims: WHAT I CLAIM IS : 1. A process for abstracting a CIO hydroxy, acyloxy or sulfonyloxy substituent from a taxane comprising reacting the CIO hydroxy, acyloxy or sulfonyloxy substituted taxane with samarium diiodide. 2. The process of claim 1 wherein the taxane corresponds to the formula: wherein R-i is hydrogen, hydroxy, protected hydroxy or together with R 14 forms a carbonate; R 2 is hydrogen, hydroxy, -OCOR 31 , or together with R 2a forms an oxo; R 2a is hydrogen or together with R 2 forms an oxo; R 4 is hydrogen, together with R 4a forms an oxo, oxirane or methylene, or together with R 5a and the carbon atoms to which they are attached form an oxetane ring; R 4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR 30 , or together with R 4 forms an oxo, oxirane or methylene; R 5 is hydrogen or together with R 5a forms an oxo; R 5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R 5 forms an oxo, or together with R 4 and the carbon atoms to which they are attached form an oxetane ring; R 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6a forms an oxo; R 6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6 forms an oxo; R 7 is hydrogen or together with R 7a forms an oxo; R 7a is hydrogen, halogen, protected hydroxy, -OR 28 , or together with R 7 forms an oxo; R 10 is hydroxy, acyloxy or sulfonyloxy; R 13 is hydroxy, protected hydroxy or R 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R- L forms a carbonate; R 14a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; R 28 is hydrogen, acyl, hydroxy protecting group or a functional group which increases the solubility of the taxane derivative; R 29 , R 30 and R 31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl; Xj is -0X 6 , -SX 7 , or -NX 8 X 9 ; X 2 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X 3 and X 4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X 5 is -COX 10 , -COOX 10 , -COSX 10 , -CONX 8 X 10 , or -S0 2 X n ; X 6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative; X 7 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group; X 8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, • aryl or heteroaryl; X 9 is an amino protecting group; X 10 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl; X ι: is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OX 10 , or -NX 8 X 14 ; and X 14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl. 3. The process of claim 2 wherein the taxane has a CIO hydroxy substituent. 4. The process of claim 1 wherein the taxane has a CIO hydroxy substituent. 5. The process of claim 2 wherein the taxane has a CIO acetoxy substituent. 6. The process of claim 2 wherein the taxane has a CIO acetoxy substituent. 7. The process of claim 1 wherein the taxane has the formula HOllll wherein Ac is acetyl and pH is phenyl 8. The process of claim 1 wherein the taxane has the formula tBu or wherein Ac is acetyl, Ph is phenyl, tBu is tert-butyl and Ac is acetyl. 9. The process of claim 2 wherein the taxane has the formula wherein R 7a is hydrogen, hydroxy, protected hydroxy or -OR 28 ; R 10 is hydroxy or acetoxy; R 13 is hydroxy, protected hydroxy or R 28 is acyl; R 30 is alkyl; R 31 is monocyclic aryl; and Xj - X 5 are as defined in claim 2.

Inventors: CHAI KI-BYUNG, HOLTON ROBERT A, SOMOZA CARMEN, CHAI, KI-BYUNG, HOLTON, ROBERT, A., SOMOZA, CARMEN
Applicants: CHAI KI BYUNG, HOLTON ROBERT A, SOMOZA CARMEN, UNIV FLORIDA STATE, CHAI, KI-BYUNG, FLORIDA STATE UNIVERSITY, HOLTON, ROBERT, A., SOMOZA, CARMEN
Application year: 1994
Main classification: C07D305
IPC codes: A61K31, A61P35, C07C233, C07C271, C07C323, C07C327, C07D305, C07D407, C07D409, C07F7